TY - JOUR T1 - Structural Characterization of in Vivo Rat Glutathione Adducts and a Hydroxylated Metabolite of Simvastatin Hydroxy Acid JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 225 LP - 230 DO - 10.1124/dmd.30.3.225 VL - 30 IS - 3 AU - Raju Subramanian AU - Xiaojun Fang AU - Thomayant Prueksaritanont Y1 - 2002/03/01 UR - http://dmd.aspetjournals.org/content/30/3/225.abstract N2 - Simvastatin hydroxy acid (SVA), the pharmacologically active form of simvastatin (SV), is a potent inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase and is formed on hydrolysis of the orally administered SV. In this article, we report the structural characterization of two new dihydroxy glutathione adducts and a trihydroxy derivative of SVA, all found in rat bile. Metabolite I is 5′β,6′β-dihydroxy-4′aα-glutathione-SVA, and metabolite II is a pentanoic acid derivative of metabolite I. The two identified GSH conjugates accounted for 16 and 9% in males and 11 and 5% in females of the total radioactivity (metabolites I and II, respectively). Metabolite III is 3′,5′β,6′β-dihydrotriol-SVA and accounts for 2% (male) and 4% (female) of the total dose in rats. Of these three newly identified metabolites, only metabolite III was also observed in dog bile. The American Society for Pharmacology and Experimental Therapeutics ER -